The present invention relates to a novel sulfonamide derivative exhibiting excellent effects in the treatment of peptic ulcer and a drug comprising the derivative as an active ingredient.
Drug therapy for peptic ulcers has been founded on two essential approaches based on Shay""s Balance Theory; inhibition of aggressive factors and potentiation of defensive factors. On the basis of such balance theory, peptic ulcers have been treated for a long time using inorganic drugs such as antacids or by mucosal protective drugs such as isoprene compounds. In the 1980s, a guanidine derivative was developed as an H2-receptor antagonist (hereinafter referred to as xe2x80x9cH2-RAxe2x80x9d), an acid secretion inhibitory drug which acts immediately and exhibits a high cure rate as compared with conventional drugs. In addition, in the 1990s, a sulfinylbenzimidazole derivative was developed as a proton pump inhibitor (hereinafter referred to as xe2x80x9cPPIxe2x80x9d) which is an acid secretion inhibitory drug having different active sites. PPIs exhibited excellent inhibitory gastric acid secretion as compared with H2-RAs. In addition, PPIs were reported to exhibit protective effects on the mucosa and to also eliminate Helicobacter pylori (hereinafter referred to as xe2x80x9cHPxe2x80x9d) which is considered to be a cause of peptic ulcer recurrence. Therefore, the development of peptic ulcer remedies was thought to have reached a culmination.
However, since both H2-RAs and PPIs, which were generally expected to successfully address the treatment of peptic ulcers, have become widely used, it has become apparent that ulcers frequently recur at a high recurrence ratio after H2-RAs is withdrawn when ulcers are thought be cured. In addition, it has been reported that when a PPI is used continuously, hyperplasia of enterochromaffin-like cells, hypergastrinemia, or gastric carcinoid may occur. Therefore, the amount of PPI to be administered has been restricted. Meanwhile, it has been pointed out that an H2-RA or PPI exhibits insufficient or no anti-HP effect when used as monotherapy, and thus it has been proposed that an H2-RA or PPI be used in combination with an antibacterial drug such as clarithromycin. On the basis of this proposition, clinical trials have been carried out using an H2-RA or PPI in combination with a variety of antibacterial drugs. However, such combination therapy for peptic ulcer has not yet become generally established, since the level of elimination of HP does not increase commensurately with the number of drugs employed; a high dose of an antibacterial drug is required; side effects may develop; and resistant bacteria may occur. In addition, peptic ulcer therapy using an H2-RA or PPI in combination with two types of antibacterial drugs, i.e., triple therapy, has also been proposed. However, at the present time, a peptic ulcer remedy exhibiting significant anti-HP effects has not been developed. H2-RAs or PPIs also have such disadvantages as a correlation between free radicals thereof and lesions of the gastric mucosa. Therefore, although H2-RAs or PPIs exhibit a gastric acid secretion inhibitory effect, both are unsatisfactory as peptic ulcer remedies.
In view of the foregoing, an object of the present invention is to provide a compound which exhibits a gastric acid secretion inhibitory effect, anti-HP effect, and a gastric mucus secretion potentiating effect, and which is useful as a peptic ulcer remedy.
The present inventors have performed extensive studies, focusing on aromatic sulfonamide compounds, and have found that a sulfonamide derivative, represented by the following formula (1), exhibits an excellent gastric acid secretion inhibitory effect, anti-HP effect, and gastric mucus secretion potentiating effect as compared with aminobenzyl derivatives disclosed in the patent application previously filed by the present inventors (Japanese Patent Application Laid-Open (kokai) No. 6-72979), and that the sulfonamide derivative is useful as a peptic ulcer remedy. The present invention has been accomplished on the basis of these findings.
Accordingly, the present invention provides a sulfonamide derivative represented by the following formula (1): 
[wherein A represents a nitrogen atom or a group xe2x80x94C(R1)xe2x95x90;
Z represents a single bond, an oxygen atom, a sulfur atom, an imino group, xe2x80x94N(R2)xe2x80x94(CH2)nxe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)nxe2x80x94N(R3)xe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)xe2x80x94Sxe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)nxe2x80x94NHSO2xe2x80x94, xe2x80x94N(R2) xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94O(CH2)nxe2x80x94N(R3)xe2x80x94, or xe2x80x94N(R2)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94CH2xe2x80x94;
Ar1 represents an aromatic hydrocarbon group, or a saturated or unsaturated heterocyclic group;
Ar2 represents a phenyl group, an alkyl group, a naphthyl group, a quinolyl group, an isoquinolyl group, a thienyl group, or a pyridyl group, which may have one through three substituents selected from among a halogen atom, an alkyl group, an alkoxy group, an acetamido group, and a nitro group;
Ra represents a hydrogen atom, a morpholinoyl group, an alkoxy group, or an aminoalkoxy group;
Rb represents a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group;
Rc represents a hydrogen atom, or an alkyl group or a halogenobenzenesulfonyl group, which may have a substituent;
R1 represents a hydrogen atom, or R1 and R2 together form a trimethylene group;
R2 represents a hydrogen atom, an alkyl group, a dialkylaminoalkyl group, a benzyl group, a halogenophenyl group, or a halogenobenzenesulfonyl group, R2 and R1 together form a trimethylene group, or R2 and R3 together form an ethanedioyl group or an alkylene group;
R3 represents a hydrogen atom, an alkyl group, a hydroxyoxalyl group, an alkanoyl group, a sulfonyl group, an alkoxycarbonyl group, or a halogenobenzenesulfonyl group, or R3 and R2 together form an ethanedioyl group or an alkylene group;
n is a number of 2-4; and
Z is not xe2x80x94N(R2)xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94 when Ar2 is an isoquinolyl group], or a salt thereof.
The present invention also provides a drug comprising, as an active ingredient, a sulfonamide derivative represented by formula (1) or a salt thereof.
The present invention also provides a pharmaceutical composition comprising a sulfonamide derivative represented by formula (1) or a salt thereof and a pharmaceutically acceptable carrier therefor.
The present invention also provides use of a sulfonamide derivative represented by formula (1) or a salt thereof as a drug.
The present invention also provides a method for treating peptic ulcer comprising administration of an effective dose of a sulfonamide derivative represented by formula (1) or a salt thereof.
In formula (1), A represents a nitrogen atom or a group xe2x80x94C(R1)xe2x95x90. When A is a nitrogen atom, a pyridine ring is formed; when R1 is a hydrogen atom, a benzene ring is formed; and when R1 and R2 together form a trimethylene group, a tetrahydroquinoline ring is formed.
In a group represented by Z in formula (1), a halogen atom of a halogenophenyl group or a halogenobenzenesulfonyl group represented by R2 or R3 may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. In R2 and R3, the alkyl group or the alkyl moiety of the dialkylaminoalkyl group is preferably a C1-C4 alkyl group. Specific examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, and a t-butyl group. Of these, a methyl or ethyl group is preferable, and a methyl group is more preferable. An alkoxy moiety of an alkoxycarbonyl group is preferably a C1-C4 alkoxy group. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, and a t-butoxy group. Of these, a t-butoxy group is preferable; and a t-butoxycarbonyl group is preferable as an alkoxycarbonyl group. Examples of alkylene groups formed by R2 and R3 include a methylene group, an ethylene group, and a trimethylene group. Of these, an ethylene group or a trimethylene group is preferable.
A number n of a group represented by Z is 2 to 4, but 2 or 3 is preferable.
Z specifically represents a single bond, an oxygen atom, a sulfur atom, an imino group (xe2x80x94NHxe2x80x94), xe2x80x94N(R2)xe2x80x94(CH2)2xe2x80x94, xe2x80x94N(R2) xe2x80x94(CH2)3xe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)2xe2x80x94N(R3)xe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)3xe2x80x94N(R3)xe2x80x94, xe2x80x94N(R2) xe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)3xe2x80x94Oxe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)2xe2x80x94Sxe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)3xe2x80x94Sxe2x80x94, xe2x80x94N(R2)xe2x80x94(CH2)2xe2x80x94NHSO2xe2x80x94, xe2x80x94N(R2)xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94O(CH2)2xe2x80x94N(R3)xe2x80x94, xe2x80x94O(CH2)3xe2x80x94N(R3)xe2x80x94, or xe2x80x94N(R2)xe2x80x94(CH2)2xe2x80x94Oxe2x80x94CH2xe2x80x94.
Examples of ethanedioyl and alkylene groups formed by R2 and R3 include the following groups. 
When Ar2 is an isoquinolyl group, Z is not xe2x80x94N(R2)xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94.
In formula (1), the aromatic hydrocarbon group represented by Ar1 may be a phenyl group or a naphthyl group, but a phenyl group is preferable. A heterocyclic group may be saturated or unsaturated. A hetero atom of the heterocyclic group may be a nitrogen atom, an oxygen atom, or a sulfur atom. Specific examples of the heterocyclic group include a pyridyl group, a thienyl group, a furyl group, a pyrimidyl group, an indolyl group, an imidazolyl group, a cumalinyl group, a phthalimidyl group, a quinolyl group, a tetrazolyl group, a triazolyl group, an oxazolyl group, a thiazolyl group, a thiadiazolyl group, a morpholino group, and a piperazino group. Of these, a morpholino group or a piperazino group is preferable. When Z is a single bond, Ar1 is preferably a morpholino group or a piperazino group.
In Ar2 in formula (1), the alkyl group is preferably a C1-C20 alkyl group. Specific examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, an n-hexyl group, an i-hexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, an n-decyl group, an n-undecyl group, an n-dodecyl group, an n-tridecyl group, an n-tetradecyl group, an n-pentadecyl group, an n-hexadecyl group, an n-heptadecyl group, an n-octadecyl group, an n-nonadecyl group, and an n-eicosyl group. Of these, a C1-C8 alkyl group is preferable. A substituent of a phenyl group may be an alkyl group similar to that as described above, but is preferably a C1-C4 alkyl group, more preferably a methyl group or an ethyl group. A halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. An alkoxy group is preferably a C1-C4 alkoxy group. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, and a t-butoxy group. Of these, a methoxy group is preferable.
In formula (1), the alkoxy group or the alkoxy moiety of the aminoalkoxy group represented by Ra or an alkoxy group represented by Rb is preferably a C1-C4 alkoxy group. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, and a t-butoxy group. The alkyl group represented by Rb or Rc is preferably a C1-C8 alkyl group. Specific examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, an n-hexyl group, an i-hexyl group, an n-heptyl group, an i-heptyl group, an n-octyl group, and an i-octyl group. Of these, Rb is preferably a methyl group, and Rc is preferably a methyl group, an ethyl group, or an n-propyl group. The halogen atom represented by Rb or the halogen atom moiety of the halogenobenzenesulfonyl group represented by Rc may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The alkyl group represented by Rc may have a substituent. Examples of substituents include an amino group; a dialkylamino group (preferably, a di-C1-4 alkylamino group such as a dimethylamino group or a diethylamino group); an aminoalkoxy group (preferably, an amino-C1-4 alkoxy group); a dialkylaminoalkoxy group (preferably, di-C1-4 alkylaminoalkoxy group); a heterocyclic group such as a pyrilidino group, a pyridyl group, a piperidino group, a piperazino group, a morpholino group, or an imidazolyl group; a hydroxyl group; a 2-cyano-3-C1-4 alkylguanidino group; a C1-4 alkoxyoxalylamino-C1-4 alkoxy group; a C3-6 cycloalkylureido-C1-4 alkoxy group; a guanidino group; a halogenophenyloxy group; a C1-4 alkoxycarbonylamino group; a halogen atom; a mono-C1-4 alkylamino group; a hydroxy-C1-4 alkylamino group; and a C1-4 alkoxycarbonylamino-C1-4 alkoxy group. A C1-4 alkyl group in these substituents may be a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, or a t-butyl group. A C1-4 alkoxy group in these substituents may be a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or a t-butoxy group.
Rc is preferably an alkyl group having a substituent selected from among an amino group, a dialkylamino group, an aminoalkoxy group, a dialkylaminoalkoxy group, a heterocyclic group, and a hydroxy group.
In formula (1) representing a sulfonamide derivative, Z is preferably xe2x80x94NH(CH2)nOxe2x80x94, xe2x80x94NH(CH2)nNH, xe2x95x90N(CH2)nNxe2x95x90, xe2x95x90N(CH2)nOxe2x80x94, or an oxygen atom. Ar1 is preferably a phenyl group. Ar2 is preferably a halogenophenyl group, more preferably a chlorophenyl group. Ra is preferably a hydrogen atom. Rb is preferably a halogen atom, more preferably a chlorine atom. Rc is preferably a dimethylaminoethyl group, an aminoethoxyethyl group, a piperidylethyl group, an aminopentyl group, a hydrogen atom, a pyrrolidylethyl group, or an aminoethyl group.
The salt of the sulfonamide derivative (1) of the present invention is not particularly limited, so long as the salt is pharmaceutically acceptable. Examples of preferred salts include salts of alkali metal and alkaline earth metal such as sodium salts, potassium salts, and calcium salts; hydrogen halide salts such as hydrogen fluorides, hydrochlorides, hydrogen bromides, and hydrogen iodides; inorganic salts such as carbonates, nitrates, perchlorates, sulfates, and phosphates; lower alkylsulfonates such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; arylsulfonates such as benzenesulfonates and p-toluenesulfonates; organic acid salts such as fumarates succinates, citrates, tartrates, oxalates, and maleates; and amino acid salts such as glutamates and aspartates.
The present invention encompasses hydrates, a variety of pharmaceutically acceptable solvates, and crystal forms of the sulfonamide derivative.
The sulfonamide derivative (1) of the present invention may be produced through, for example, the following process (1). 
(wherein X represents a halogen atom, Rc represents an alkyl group which may have a substituent, and A, Z, Ar1, Ar2, Ra, and Rb are the same as described above).
Briefly, when an amine compound (2) is reacted with a sulfonyl halide (3), a monosulfonamide (1a) and a disulfonamide (1b) are obtained. Subsequently, when a monosulfonamide (1a) is reacted with an alcohol (4), a compound (1c) is obtained.
In the process, the reaction between the compound (2) and the sulfonyl halide (3) is preferably carried out in the presence of a base such as pyridine in a manner similar to the reaction of customary acid amid formation. In the process, the reaction between the compound (1a) and the alcohol (4) may be carried out through the Mitsunobu process by use of triphenylphosphine and diisopropylazo dicarboxylate. However, the reaction is preferably carried out through a customary process; i.e., a reaction between a halogenated alcohol and an alkali metal salt of amide, or a reaction between a sulfonated alcohol and an alkali metal salt of amide.
The amine compound (2) serving as a raw material in the process can be produced as follows. The group Rbxe2x80x94Ar1xe2x80x94Zxe2x80x94 is introduced into phenylenediamine, nitrobenzene, or nitropyridine, serving as a raw material, and then the nitro group of the resultant compound is reduced to an amino group.
Of sulfonamide derivatives (1) of the present invention, compounds in which Z and Ra moieties have special structures may be produced as follows: 
(wherein A, Ar1, Ar2, Ra, Rb, and Rc are the same as described above).
When a compound (1d) is reacted with oxalyl chloride, a compound (1e) in which Z is a piperazinedione structure.
A variety of salts of the thus-produced compound of the present invention can be obtained through a conventional process.
The sulfonamide derivative of the present invention exhibits a gastric acid secretion inhibitory effect, anti-ulcer effect, radical scavenging effect, gastric mucus secretion potentiating effect, and anti-HP effect, and thus the derivative is effectively employed as a peptic ulcer remedy.
A drug comprising the sulfonamide derivative (1) of the present invention may be administered orally or parenterally. The drug may be formed into a variety of products including oral administration forms such as powders, granules, tablets, sugar-coated tablets, and capsules; subcutaneous, intramuscular, or intravenous injections; and suppositories.
The aforementioned drug products may be produced by use of the sulfonamide derivative (1) singly, or by use of the derivative in an appropriate combination with pharmaceutically acceptable carriers such as excipients, expanders, binders, wetting agents, disintegrating agents, surfactants, lubricants, dispersants, buffers, preservatives, sweetening agents, perfumes, and coating agents.
The dose of the thus-produced drug of the present invention varies depending on the disease to be treated, symptoms, or administration route. One daily dose of the drug for an adult is usually 3-1,000 mg as reduced to the sulfonamide derivative (1), preferably 10-500 mg. The aforementioned daily dose is preferably administered in divided portions 1-4 times a day.